CCR8 Targeting: A Promising Strategy for Cancer Immunotherapy and Beyond

Introducing Chemokine Receptor 8 and its role in immune cell trafficking


Allow me to introduce CCR8 and its significant role in the trafficking of immune cells. CCR8, a G protein-coupled receptor belonging to the chemokine receptor (CCR) family, plays a vital role in coordinating the movement of immune cells towards areas of inflammation and infection. This intricate process, known as immune cell trafficking, is of utmost importance in initiating and resolving adaptive immune responses. The main ligand for CCR8 is CCL1 (1), a chemokine that is produced by both immune and non-immune cells, with a particular abundance in the skin and mucosal tissues. The interaction between CCR8 and CCL1 effectively guides the migration of immune cells expressing CCR8, such as T cells, dendritic cells (DCs), and monocytes, towards these specific tissues.


CCR8 and Immune Cell Recruitment to Skin and Mucosal Tissues


The skin and mucosal surfaces serve as the primary defense against invading pathogens, with CCR8 playing a crucial role in coordinating the immune response in these highly exposed tissues. In the skin, CCR8-positive dendritic cells (DCs) are essential in initiating Th2-mediated allergic responses when exposed to allergens.


These CCR8-positive DCs migrate from the skin to lymph nodes, where they activate naive T cells to differentiate into Th2 cells, which are characteristic of allergic inflammation.


Similarly, CCR8 plays a vital role in mucosal immune responses by guiding the recruitment of CCR8-positive immune cells to mucosal tissues, such as the gut and lungs. These cells play a pivotal role in preserving the integrity of the mucosal barrier and preventing the invasion of pathogens.


CCR8 and Immune Cell Polarization


The expression of CCR8 has been shown to play a significant role in the activation of immune responses, particularly in promoting a Th2-biased phenotype. Th2 cells, a specialized group of T cells, release powerful inflammatory cytokines that are crucial in triggering allergic reactions. The presence of CCR8 on dendritic cells (DCs) enhances their ability to drive the differentiation of Th2 cells, thus contributing further to the development of allergic inflammation. This groundbreaking discovery suggests that targeting CCR8 could hold great promise for the treatment of allergies and other conditions mediated by Th2 responses.


CCR8 in Cancer Immunotherapy


Tumor-associated regulatory T cells (Tregs), a subset of T cells that suppress the immune response, also express CCR8. CCR8 expression on Tregs allows them to migrate to tumor sites and suppress the antitumor immune response. Targeting CCR8 with anti-CCR8 monoclonal antibodies has shown promising results in preclinical studies, suggesting that CCR8 may be a viable therapeutic target for cancer immunotherapy.


Therapeutic applications of CCR8 targeting, a growing interest


CCR8-targeted therapies may work in different disease areas, by targeting regulatory T cells (Tregs) or chemokine receptor that is highly expressed on Type (ILC2s):

  • Allergies: CCR8 is a chemokine receptor that is highly expressed on ILC2s, allowing them to migrate to sites of inflammation and infection. ILC2s resemble type 2 helper (Th2) cells in cytokine production and contribute to anti-helminth immunity, maintaining mucosal tissue integrity and adipose tissue browning. Targeting CCR8 on ILC2s can inhibit ILC2 activation and reduce allergic inflammation (1).
  • Autoimmune diseases: Suppressing CCR8 expression on ILC2s can dampen the excessive immune response that characterizes autoimmune diseases. This may lead to reduced disease activity and improved quality of life for patients with autoimmune diseases.
  • Inflammatory diseases: Blocking CCR8 expression on inflammatory monocytes can reduce their recruitment to sites of inflammation and dampen the inflammatory response.
  • Cancer: In cancer, CCR8 expression on Tregs contributes to tumor immune evasion by suppressing the antitumor immune response. Blocking CCR8 expression on Tregs can deplete these cells and enhance the antitumor immune response.